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NIH Notice on Dissemination of Clinical Trial Information

Friday, September 23, 2016   (0 Comments)
Posted by: Whitney Lingafelter
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The National Institutes of Health (NIH) is issuing this policy

to promote broad and responsible dissemination of information from NIH-funded clinical trials through ClinicalTrials.gov. The policy establishes the expectation that all investigators conducting clinical

trials funded in whole or in part by the NIH will ensure that these

trials are registered at ClinicalTrials.gov, and that results

information of these trials is submitted to ClinicalTrials.gov.

DATES: This policy will take effect January 18, 2017.

FOR FURTHER INFORMATION CONTACT: For information about the policy, please contact the NIH Office of Science Policy at

clinicaltrials.disseminationpolicy@mail.nih.gov.

SUPPLEMENTARY INFORMATION: The policy is complementary to the statutory and regulatory reporting requirements. These are section 402(j) of the

Public Health Service Act, as amended by Title VIII of the Food and

Drug Administration (FDA) Amendments Act of 2007 (FDAAA), and the

regulation Clinical Trial Registration and Results Information

Submission, at 42 CFR part 11. Hereafter, we refer to section 402(j) as

the statute and 42 CFR part 11 as the rule or regulation.

    On November 19, 2014, and in tandem with the publication of the

Notice of Proposed Rulemaking (NPRM) on Clinical Trial Registration and Results Submission, the NIH issued a complementary draft policy for public comment on the Dissemination of NIH-funded Clinical Trial

Information [Ref. 1, 2]. The draft policy proposed that all NIH-funded

awardees and investigators conducting clinical trials, funded in

[[Page 64923]]

whole or in part by the NIH, regardless of study phase, type of

intervention, or whether they are subject to the statutory registration

and results information submission requirements, would be expected to

ensure that those clinical trials are registered and results

information is submitted to ClinicalTrials.gov. It further stated that

submission of the same type of registration and results information

would be expected and in the same timeframes as the trials subject to

the statute, and that this information would be made publicly available

through the ClinicalTrials.gov Web site.

    The NIH received approximately 240 public comments on its proposed policy. The comments came from a range of stakeholders including researchers, academic/research institutions, medical practitioners, patients, patient/disease advocacy groups, scientific/professional societies and associations, device manufacturers, trade associations, not-for-profit non-governmental organizations, and the general public [Ref. 3]. The NIH appreciated the public interest in the proposed policy and the time made and effort taken by stakeholders to provide comments. The NIH carefully considered those comments in the development of the final policy. In the next section, we provide an overview of the comments on the proposed policy. Because those in compliance with the policy would be expected to follow specific provisions of the rule, a number of commenters on the policy reiterated comments that they submitted to the docket in response to the NPRM [Ref. 4]. Since these comments are discussed at length in the preamble of the rule, we are limiting the discussion of comments here primarily to those that identified issues specific to the policy, such as its scope, applicability, and impact on NIH-funded awardees and investigators. 

Overview of the Public Comments

     A significant majority of the public comments were supportive of

the proposed NIH policy and of its application to the full range of

NIH-funded clinical trials. Most commenters appreciated the impetus

behind the policy and agreed that it was important to provide ways

other than journal publication for clinical trial results to be

disseminated and made publicly available to researchers, health care

providers, and patient communities. They recognized that increased

availability of information from NIH-funded clinical trials would help

researchers by informing the design and development of their future

studies, address the needs of patients and healthcare providers seeking information about NIH-funded trials, and serve the public's interest by preventing duplication of unsafe and unsuccessful trials and mitigating publication bias. They also agreed that improving the availability of clinical trial information will strengthen the public's trust in

biomedical research as well as assure volunteers that their

participation in clinical trials has advanced knowledge on human health

and disease. A number of commenters also suggested that the policy is particularly appropriate because NIH-funded clinical trials are

supported by public funding, and recipients of those funds have a

special obligation to ensure that the nation's investment is maximized.

    A number of comments from academic investigators and stakeholder  organizations were supportive of the policy and its goals. Others,

however, disagreed with the policy, suggesting that it was ill-advised

and/or unnecessary. These commenters suggested that the benefit of

greater transparency was outweighed by the burden and cost of the

policy to those who conduct clinical trials and that the NIH had not

made a sufficient case for the policy or that it was not evidence-

based. Some commenters suggested that the NIH should simply encourage

investigators to be more transparent or that the NIH's public access

policy made the policy unnecessary since it requires NIH-funded

investigators to make their published articles publicly available

through PubMed Central.

    Scope and Applicability of the Policy. Although the majority of

commenters fully supported the scope of the policy, i.e., that it

should apply to NIH-funded clinical trials of FDA-regulated drugs

regardless of phase, small feasibility studies of devices, and trials

of interventions not regulated by FDA, including surgical and

behavioral interventions, there were comments suggesting that the scope was too narrow, or conversely, too broad.

    One commenter suggested that the policy ought to encompass more detailed summary results, such as Clinical Study Reports, as well as

de-identified individual patient-level data. One commenter suggested

that the NIH should consider extending the policy to preclinical in

vivo (laboratory) animal studies because the arguments for the

registration and required reporting of preclinical in vivo (laboratory)

animal studies are similar to those of human clinical trials. Some

commenters suggested that the policy should be retroactive and apply to clinical trials that are underway as of the policy's effective date as

well as those that have already been completed as of the effective

date.

    On the other hand, there were other comments suggesting that the

policy should not apply to phase 1 or so called phase 0 trials, pilot

trials designed to examine the feasibility of an approach, trials

mounted by an investigator at a small organization, or trials that are

unable to enroll a statistically significant number of participants.

One suggested that even pilot trials that reach their enrollment target

should not be expected to submit results information because the

results might be more misleading than helpful. Another proposed that

reporting on phase 1 clinical trials should be limited to adverse

events information because these trials are designed to assess safety

rather than efficacy, and reporting non-safety outcomes could be

misleading. Another suggested that clinical trials not covered under

the statute should not submit adverse event information unless a

regulatory authority or equivalent body has first performed an analysis

of the event in order to prevent public misunderstanding. Another

commenter suggested that submission of data from early phase research could divert limited research resources and time from phase 3 studies. Another suggested that only information about phase 3 clinical trials should be included in ClinicalTrials.gov because information about

early stage trials could confound, rather than enhance, public

understanding of human health and could, thereby, inadvertently

adversely affect patient safety.

    One commenter suggested that the policy should apply only to the

registration of clinical trials, not the submission of results

information. This commenter asserted that registration information was

sufficient because any interested party could follow up with an

investigator to learn more about the trial and because submission of

registration information takes a fraction of the time needed to submit

results information.

    There were a few commenters who took issue with the application of

the policy to trials that are only partially funded by the NIH. They

asserted that the policy would entail the disclosure of confidential

commercial information and that the NIH's authority to do so is limited

to a trial that is wholly NIH-funded and involves a product with

research and development costs wholly government-funded. A few other commenters suggested that the policy should exclude clinical trials that use NIH-supported infrastructure, but involve no NIH funds.

[[Page 64924]] 

    NIH Definition of Clinical Trial. Some commenters addressed the NIH 

definition of clinical trial, which is key to determining the policy's

applicability. There was support for the breadth of the definition,

i.e., encompassing all interventional studies with biomedical outcomes

(e.g., pharmacokinetic and behavioral outcomes, as well as health-

related outcomes). One commenter, however, thought more elaboration on

the definition was needed to clarify the meaning of ``health-related

biomedical or behavioral outcomes.'' They thought that without such

specificity, the definition might be interpreted to exclude studies

that contain valuable information for public health research, science,

and clinical medicine. Commenters believed that addressing this issue

would be vital to ensure a common understanding that the NIH policy

applies to all clinical trials involving a biomedical or behavioral

intervention. Another suggested that a study involving only one

participant should not be considered a clinical trial since a trial

with a sample size of one would not provide any valid data to share

with the public.

    Some commenters noted that the wording of the NIH definition was

not identical to the wording of the definition of clinical trial in the

proposed rule or to how other organizations, e.g., the World Health

Organization (WHO), International Committee of Medical Journal Editors (ICMJE), and Centers for Medicare & Medicaid Services (CMS), use the term. They were concerned that investigators would have difficulty understanding their obligations under the policy and under the rule and in meeting requirements of others. They called for reconciliation of any actual or apparent differences in the definitions.

    A commenter urged the NIH to issue guidance to help determine

whether a study is a clinical trial under the definition and to clarify

how disagreements in the matter would be resolved and communicated.

    Results Information Submission Timeline. A few commenters raised

concerns about the proposed rule's timeline for reporting results

information, asserting that 12 months after the primary completion date

of the clinical trial (i.e., the date of final data collection for the

primary outcome measure) is too soon, particularly for NIH-funded

academic investigators. These commenters suggested that academic

investigators will have more difficulty meeting the timeframe because

they must also spend time teaching, fulfilling clinical care

responsibilities, and writing grant applications. Another commenter

suggested that a 12-month timeframe would also be more challenging for academic investigators because, unlike industry investigators, they

generally cannot count on support from a central administrative service

to help them carry out their reporting responsibilities.

Decentralization of information in academic centers would also present

a particular challenge to those covered by the NIH policy, according to

another commenter, who also suggested that the mobility of new

investigators may make it difficult to meet timelines. These commenters urged the NIH to allow a longer submission timeframe, e.g., 18 or 24 months. A few noted that providing more time would also give investigators time to prepare journal publications, and one also

expressed concern about the possibility that journal editors will begin

to consider submission of results information to ClinicalTrials.gov as

prior publication, which could thwart journal publication altogether.

    Structured Results Data Elements. A few commenters suggested that the data submission structure, which is determined by the provisions of the statute, does not work well for clinical trial types that will be covered only the policy, e.g., phase 1 trials of drugs/biologics, small feasibility device studies, trials of social and behavioral

interventions, or those with non-standard designs. These commenters

thought that other fields would need to be added to the

ClinicalTrials.gov to enable investigators to report data elements for

those trials appropriately and accurately. They also suggested

increasing the character limit on data fields to allow for more careful

and nuanced explanations. Commenters also suggested that if the

ClinicalTrials.gov cannot accommodate these types of trials,

investigators should be exempted from the policy. One commenter

requested that an additional data element should be included to allow

an investigator to indicate that the trial's hypothesis had been

confirmed.

    Protecting Privacy. One commenter raised a concern about the

policy's impact on the privacy of clinical trial participants

suggesting that it might be easy to re-identify participants in many

NIH-funded pilot studies with small sample sizes. The commenter pointed to the five percent threshold for non-serious adverse events and site location information as the data elements creating the vulnerability.

The commenter urged the NIH to allow an investigator to obtain a waiver from results information submission where participant privacy was at risk.

    Compliance Issues. The proposed policy noted that compliance with

the policy would be a term and condition of award and that non-

compliance may provide a basis for enforcement actions, including

termination. A few commenters discussed the importance of compliance.

One suggested that the NIH should take compliance records into account

when considering future applications for funding. They suggested that

such an approach could be more effective than terminating funding of a

current grant since most of the research may already be completed.

Another thought that making compliance a term and condition of award

was important and that it would incentivize good behavior and help

change attitudes about the value of enhancing availability of clinical

trial information.

    Other commenters raised concerns about the costs that will be

incurred by NIH-funded academic institutions to ensure that clinical

investigators are following the policy. They suggested institutions

will need to provide more administrative support and other resources to

help investigators comply and that this would be difficult given the

indirect cost cap of 26 percent. Commenters urged the NIH to allow the

time and effort required for ClinicalTrials.gov compliance to be

included as a direct cost on NIH grants. Another commenter suggested

that the increased results information submissions brought on by the

NIH policy will stretch the NIH's capabilities and that it will be

important for the NIH to ensure that sufficient resources are available

to manage high volume data uploads and customer service requests.

 

NIH Policy

 

    The NIH considered all the comments received on the proposed policy

as well as those that were submitted in response to the NPRM. There was

overwhelming support for both the proposed policy and the NPRM,

particularly among concerned citizens, scientific societies, medical

practitioners, and individual scientists. There were also concerns

expressed, particularly in the comments from academic commenters. We

appreciate those concerns and understand that the policy will create

additional work for many investigators. However, we believe that the

work should not be seen as a burden, but, rather, an inherent part of

an investigator's commitment to the advancement of science. The

benefits will, in the long run, accrue to the investigators as well as

to the public, patients, and the enterprise as a whole because

transparency will improve

[[Page 64925]]

future research designs and maximize the public's investment--and their 

trust--in research. Equally important, it will help investigators

fulfill the ethical obligation they have to clinical trial

participants, namely to ensure that the findings from their

participation contribute to generalizable knowledge and the advancement

of public health.

    As we noted in the preamble to the proposed policy, a fundamental

premise of all NIH-funded research is that the results of such work

must be disseminated in order to contribute to the general body of

scientific knowledge and, ultimately, to the public health. The NIH

awardees have always been expected to make the results of their

activities available to the research community and to the public at

large because it is intrinsic to the scientific process. In research

involving human beings, moreover, scientists also have an ethical

obligation to ensure that the burden and risk that volunteers assume by

participating in research comes to something, at the very least by

ensuring that others are aware of the study and that its findings

contribute to the advancement of human health.

    We disagree with commenters who suggested that there is no need for

coverage of certain types of trials, such as early exploratory trials,

small trials, trials assessing only safety, or trials that terminate

before reaching enrollment targets. The benefits of transparency and

the need to fulfill the ethical obligation to participants is as

relevant to these types of trials as to any other type. We were also

not persuaded that the timeframe for results information submission

should be longer for academic investigators because of their competing 

responsibilities or that they should be allowed more time to publish

their results in a journal. The timeframe of 12 months from the primary

completion date should provide enough time for investigators to

organize their data and submit results information. We are also

confident that academic institutions can develop central support

services as necessary to assist investigators should they need it. We

also believe that 12 months represents an appropriate balance between

investigators' interests and the interests of the public in having

access to the results of a publicly funded trial. In addition, it will

be possible to delay results information submission for up to two years

beyond the initial deadline with a certification that regulatory

approval of the trial product is being sought.

    Some commenters suggested that a policy on clinical trial

information dissemination is not needed because it duplicates other NIH 

policies. This policy is certainly in keeping with our principles,

longstanding expectations, and other policies as well as the more

recent broad policy call for scientific agencies to increase public

access to scientific data [Ref. 5]. However, it does not duplicate any

other NIH policy, nor does any other NIH policy accomplish what this

one will.

    Some commenters also contended that this policy is not necessary

because the results of clinical trials will be published or because

they can be obtained via direct requests to the trial's principal

investigator. In fact, research has shown that the results of a

significant portion of clinical trials are not published or published

in a timely manner. For example, a 2012 study of NIH-funded clinical

trials found that after a median of 51 months following trial

completion, 32 percent were unpublished [Ref. 6]. A more recent study

of the trial publication rate among 51 U.S. academic medical centers

found that 43 percent of their clinical trials were unpublished two

years after the trial was completed [Ref. 7]. While the ability to seek

results information from the original investigator is useful to

facilitate collaborations, to access individual-level data, and to gain

insights from those who conducted the trial, it is not a surefire way

to increase access to trial results nor is it efficient or transparent,

particularly for the public.

    We believe that the public availability of clinical trial results

information will be beneficial to all parties in the long run,

including those who are covered by this policy. All investigators stand

to benefit from this policy. For example, science may progress more

quickly because investigators will be able to learn from trials to

which they otherwise would not have had access because they were

unpublished. In addition, the public availability of results

information helps investigators design trials and Institutional Review

Boards (IRBs) review proposed trials, by allowing them to weigh the

proposed study's risks and benefits against a more complete evidence

base than is currently available through the scientific literature

[Ref. 8]. Submission and posting of results information will also help

investigators avoid repeating trials on interventions that have been

found to be unsafe or unsuccessful while also providing access to

information that may help verify findings.

    For all of these reasons, we have not changed the essential

contours of the policy. In terms of scope, the policy still applies to

all NIH-funded awardees and investigators conducting clinical trials

funded in whole or in part by the NIH regardless of study phase, type

of intervention, or whether they are subject to the statute and to the

rule. It clarifies that the policy is an expectation, that applicants

and offerors are required to submit a plan outlining how they will meet

the policy's expectations, and, that upon receipt of an award, an

awardee will be obligated to adhere to their plan through the terms and

conditions of the award. The required plan can be a brief statement

explaining whether the applicant/offeror intends to register and submit

results information to ClinicalTrials.gov as outlined in the policy or

to meet the expectations in another manner. It is important to remember

that an NIH-funded clinical trial that meets the definition of an

applicable clinical trial is subject to the regulation and, therefore,

register and submission of results information to ClinicalTrials.gov is

a requirement.

    The policy applies to both the extramural and intramural programs.

For the NIH extramural program, the policy applies to applications for

funding including for grants, other transactions, and contracts

submitted on or after the policy's effective date that request support

for the conduct of a clinical trial that is initiated on or after the

policy's effective date. This means that the policy does not apply to

clinical trials in ongoing, non-competing awards, but that it will

apply if the grantee submits a competing renewal application that

includes a new clinical trial, i.e., a clinical trial initiated on or

after the effective date of the policy. For the intramural program, the

policy applies to clinical trials initiated on or after the policy's

effective date. The policy's effective date is January 18, 2017. The

policy clarifies that a clinical trial that uses NIH-supported

infrastructure, but does not receive NIH funds to support its conduct,

is not subject to the policy.

    The policy outlines the responsibilities for NIH-funded

investigators according to whether the trial is covered by the policy

only or also the rule. For those covered by the policy only, NIH-funded

awardees and investigators will be expected to submit the same

registration and results information in the same timeframes as those

subject to the statute and rule. The timeline for registration is not

later than 21 calendar days after the enrollment of the first

participant. The standard timeline for results information is not later

than one year after the trial's primary completion date, but the policy

also allows for delayed submission of results information in certain

[[Page 64926]]

circumstances for up to two additional years for trials of products

regulated by the FDA that are unapproved, unlicensed, or uncleared or

for trials of products for which approval of a new use is being sought.

    Although the policy does not apply to NIH-funded clinical trials

initiated before the effective date, we encourage all ongoing NIH-

funded clinical trials to follow it. It is also critical for

investigators conducting NIH-funded applicable clinical trials that are

subject to the statute and rule to be sure they are in compliance with

those requirements.

    The policy continues to use the NIH definition of ``clinical

trial'' as proposed in the draft policy to determine which research

studies are covered by the policy. This definition was developed in

2014 to reflect the NIH research mission and the scope of clinical

trials within the NIH portfolio. With regard to the concern expressed

by a public commenter that the phrase ``health-related biomedical or

behavioral outcomes'' might be too narrow, we note that the definition

considers biomedical and behavioral outcomes to be health-related

outcomes in interventional studies that meet the other components of

the definition. Also, regarding the concern that the wording of the

definitions of clinical trial in this policy and the rule differ, this

is so mainly in reference to outcomes, i.e., the NIH definition

explicitly references behavioral outcomes whereas the definition in the

rule encompasses them within the term ``health related.'' These

distinctions are not significant in terms of defining what is covered

by the NIH policy. All NIH-funded clinical trials, whether they are

assessing biomedical or behavioral outcomes or whether they are

employing an FDA regulated product, are covered by the policy. An NIH-

funded clinical trial assessing a behavioral intervention that is not

regulated by the FDA would meet both definitions of clinical trial,

and, thereby, be covered by the policy. However, such a trial would not

be subject to the rule because it does not meet the rule's definition

of ``applicable clinical trial.'' Guidance available on the NIH's Web

site can help awardees and investigators understand whether a research

study is a clinical trial for purposes of the NIH policy (see first Web

site listed below). Questions should be directed to the NIH program

staff. To understand whether an NIH-funded clinical trial is also

subject to the statute and the rule, awardees and investigators should

look to the rule's definition of ``applicable clinical trial.''

    NIH-funded awardees and investigators will be expected to follow

the provisions of the rule in terms of when they register their trials,

what information they provide as part of the registration process, when

they submit their results information, and what results information is

submitted. All of the alternate approaches in the rule will also be

available to those covered by the policy, e.g., for delayed posting of

device registration information, delayed submission of results

information for trials involving unapproved products or products for

which a new use is sought, extensions for good cause, and waivers that

might be needed for privacy or national security reasons.

    With regard to the concern that ClinicalTrials.gov is not set up to

accept NIH-funded trials that are small or exploratory in nature or

involve behavioral interventions, it is important to note that the

ClinicalTrials.gov does accommodate the submission of all trial types

and that a variety of study and trial types have been entered into

ClinicalTrials.gov since its inception. In addition, ClinicalTrials.gov

has resources available to assist investigators in navigating the

registration and results information submission processes. These

resources will continue to be updated over time to be responsive to

investigators' needs and the evolving clinical research enterprise.

Therefore, it should not be necessary for a clinical investigator of an

NIH-funded clinical trial to seek an exemption from the policy for

reasons related to the capacity of ClinicalTrials.gov to accommodate

all types of clinical trials.

    Registration and results information submission to

ClinicalTrials.gov complements publication of trial results in peer-

reviewed scientific journals. Information submitted to

ClinicalTrials.gov is displayed in a structured way and includes a

complete list of all pre-specified outcome measures and all adverse

events. Journal articles, on the other hand, typically focus on a

select set of outcome measures and adverse events and include

background and discussion of the implications of the results.

Information submitted to ClinicalTrials.gov undergoes a quality control

review whereas journal articles will be peer reviewed. With regard to

the concern that submission of results could make journal publication

more difficult or impossible, the ICMJE has stated that submission of

summary results to ClinicalTrials.gov will not be considered prior

publication and will, thus, not interfere with journal publication

[Ref. 9]. We encourage all NIH-funded investigators to publish the

results of their studies in peer-reviewed journals.

    We have no doubt that this policy will be beneficial for the

research community as well as the public generally, but we recognize

that adhering to it will be a new obligation. We will provide

additional guidance to facilitate implementation and help awardees and

investigators understand the policy as well as the tasks described in

the rule that they will be expected to undertake. In terms of the costs

of complying with the policy, grantees are permitted to charge the

salaries of administrative and clerical staff as a direct cost [Ref.

10]. Such staff could assist investigators in meeting their

responsibilities under the policy. In addition, administrative costs

can be covered through indirect cost recovery.

    We intend for this policy to benefit all communities who seek

information about NIH-funded clinical trials, and we are confident that

the benefits of transparency will become evident soon after the policy

is implemented. We plan to evaluate the implementation and impact of

the policy from the perspective of those who comply with it as well as

from the perspective of ClinicalTrials.gov users, including patients,

providers, and investigators.

    We look forward to engaging with NIH-funded investigators and

awardees as they work to meet the expectations of this important public

policy. Information to assist applicants, offerors, and investigators

is available at the following Web sites. The NIH will continue to add

guidance materials to these sites as the policy's implementation

continues.

     http://osp.od.nih.gov/office-clinical-research-and-bioethics-policy/clinical-research-policy/clinical-trials

     https://clinicaltrials.gov/ct2/manage-recs

     http://grants.nih.gov/clinicaltrials_fdaaa/faq.htm

 

    The NIH policy is set forth below.

References

1. National Institutes of Health, U.S. Department of Health and

Human Services, NIH request for public comments on the proposed NIHpolicy on dissemination of NIH-funded clinical trial information.

NIH Guide for Grants and Contracts. 2014 Nov 19. Available from

https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.html.

Also published in Fed Regist. 2015 Feb 13; 80(30):8096-98. Available

from https://www.federalregister.gov/articles/2015/02/13/2015-02994/announcement-of-a-draft-nih-policy-on-dissemination-of-nih-funded-clinical-trial-information.

2. National Institutes of Health, U.S.

[[Page 64927]]

 

Department of Health and Human Services, Notice of Proposed

Rulemaking on Clinical Trials Registration and Results Submission.

Fed Regist. 2014 Nov 21;79(225):69566-69680. Available from https://www.federalregister.gov/articles/2015/02/13/2015-02990/clinical-trials-registration-and-results-submission.

3. A compilation of public comments on the draft NIH Policy on

Dissemination of NIH-Funded Clinical Trial Information is available

at: http://osp.od.nih.gov/sites/default/files/resources/Clinical%20Trials%20Dissemination%20Policy%20Combined%20Comments_2.0.pdf.

4. U.S. Department of Health and Human Services, National Institutes

of Health, National Library of Medicine. Clinical Trials

Registration and Results Submission. [Internet]. 2011 [cited 2016

September 1]. Available from: https://www.regulations.gov/docket?D=NIH-2011-0003.

5. NIH Data Sharing Policy (https://grants.nih.gov/grants/policy/data_sharing/); NIH Public Access Policy (https://publicaccess.nih.gov/policy.htm or https://publicaccess.nih.gov/);

NIH Genomic Data Sharing Policy (https://gds.nih.gov/03policy2.html); Increasing Access to the Results of Federally

Funded Scientific Research (https://www.whitehouse.gov/sites/default/files/microsites/ostp/ostp_public_access_memo_2013.pdf).

6. Ross et al., BMJ. 2012 Jan 3;344:d7292. http://www.bmj.com/content/bmj/344/bmj.d7292.full.pdf.

7. Chen et al., BMJ. 2016 Feb 17;352:i637 http://www.bmj.com/content/bmj/352/bmj.i637.full.pdf.

8. Berlin, JA, et al., Bumps and Bridges on the Road to Responsible

Sharing of Clinical Trial Data. Clinical Trials. 2014;11:7-12.

9. ICMJE [Internet]. International Committee of Medical Journal

Editors; 2016. Clinical trial registration; 2011 [cited 2016 Aug 5];

[about 2 screens]. Available from: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html and http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/.

10. 45 CFR 75.413(c) and Chapter 8.1.1.6, Direct Charging Salaries

of Administrative and Clerical Staff. NIH Grants Policy Statement.

http://grants.nih.gov/grants/policy/nihgps/HTML5/section_8/8.1_changes_in_project_and_budget.htm.

NIH Policy on Dissemination of NIH-Funded Clinical Trial Information

Purpose

    The National Institutes of Health (NIH) Policy on Dissemination of

NIH-funded Clinical Trial Information establishes the expectation that

all NIH-funded awardees and investigators conducting clinical trials,

funded in whole or in part by the NIH, will ensure that their NIH-

funded clinical trials are registered at, and that summary results

information is submitted to, ClinicalTrials.gov for public posting.\1\

The purpose of the policy is to promote broad and responsible

dissemination of information from NIH-funded clinical trials through

ClinicalTrials.gov. Disseminating this information supports the NIH

mission to advance the translation of research results into knowledge,

products, and procedures that improve human health.

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    \1\ ClinicalTrials.gov is operated by the National Library of

Medicine within the NIH.

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    This policy is complementary to requirements in the Clinical Trial

Registration and Results Information Submission regulation at 42 CFR

part 11, hereinafter referred to as the regulation.\2\ Clinical trials

that are subject to the regulation are, in general, clinical trials of

drug, biological, and device products regulated by the Food and Drug

Administration (FDA), except phase 1 trials of drug and biological

products and small feasibility studies of device products. A pediatric

post-market surveillance study of a device product required by the FDA 

is also subject to the regulation. Clinical trials subject to the

regulation are generally called ``applicable clinical trials.''

Applicable clinical trials are required to be registered in

ClinicalTrials.gov not later than 21 calendar days after the enrollment

of the first participant. Results information from those trials

generally must be submitted not later than one year after the trial's

primary completion date. Submission of results information can be

delayed in certain circumstances for up to two additional years for

trials of products regulated by the FDA that are unapproved,

unlicensed, or uncleared or for trials of products for which approval,

licensure, or clearance of a new use is being sought.

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    \2\ The Clinical Trial Registration and Results Information

Submission regulation at 42 CFR part 11 was issued in the Federal

Register in September 2016. The regulation implements section 402(j)

of the Public Health Service Act.

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Scope and Applicability

    This policy applies to all NIH-funded clinical trials regardless of

study phase, type of intervention, or whether they are subject to the

regulation. For example, NIH-funded phase 1 clinical trials of an FDA-

regulated product are covered by this policy as are clinical trials

studying interventions not regulated by the FDA, such as behavioral

interventions. As such, the policy encompasses all NIH-funded clinical

trials, including applicable clinical trials subject to the regulation.

All NIH-funded clinical trials will be expected to register and submit

results information to ClinicalTrials.gov.

    This policy applies to clinical trials funded in whole or in part

through the NIH extramural and intramural programs. For the NIH

extramural program, the policy applies to applications for funding

including for grants, other transactions, and contracts submitted on or

after the policy's effective date that request support for the conduct

of a clinical trial that is initiated on or after the policy's

effective date. For the NIH intramural program, the policy applies to

clinical trials initiated on or after the policy's effective date.

    This policy does not apply to a clinical trial that uses NIH-

supported infrastructure but does not receive NIH funds to support its

conduct.

Responsibilities

    As part of their applications or proposals, applicants and offerors

seeking NIH funding will be required to submit a plan for the

dissemination of NIH-funded clinical trial information that will

address how the expectations of this policy will be met. NIH-funded

awardees and investigators conducting clinical trials funded in whole

or in part by the NIH will be required to comply with all terms and

conditions of award, including following their plan for the

dissemination of NIH-funded clinical trial information.

    Consistent with those terms and conditions, the responsibilities of

such awardees and investigators will fall within one of the three

categories. The category depends on whether, under the regulation, the

clinical trial is also an ``applicable clinical trial'' and the awardee

or investigator is the ``responsible party.''

    1. If the NIH-funded clinical trial is an applicable clinical trial

under the regulation and the awardee or investigator is the responsible

party, the awardee or investigator will ensure that all regulatory

requirements are met.

    2. If the NIH-funded clinical trial is an applicable clinical trial

under the regulation but the awardee or investigator is not the

responsible party, the awardee or investigator will coordinate with the

responsible party to ensure that all regulatory requirements are met.

    3. If the NIH-funded clinical trial is not an applicable clinical

trial under the regulation, the awardee or investigator will be

responsible for carrying out the tasks and meeting the timelines

described in regulation. Such tasks include registering the clinical

trial in ClinicalTrials.gov and submitting results information to

ClinicalTrials.gov.

 

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    In addition, informed consent documents for clinical trials within

all three categories are to include a specific statement relating to

posting of clinical trial information at ClinicalTrials.gov.

    Each NIH-funded clinical trial should have only one entry in

ClinicalTrials.gov that contains its registration and results

information. Awardees and investigators need not and should not create 

a separate record of the applicable clinical trial to comply with this

policy.

    The NIH will publicly post registration information and results

information in ClinicalTrials.gov.

Definitions

    Clinical Trial. For purposes of this policy, a ``clinical trial''

means ``a research study in which one or more human subjects are

prospectively assigned to one or more interventions (which may include 

placebo or other control) to evaluate the effects of those

interventions on health-related biomedical or behavioral outcomes.''

\3\ This definition encompasses phase 1 trials of FDA-regulated drug

and biological products, small feasibility studies of FDA-regulated

device products, and studies of any intervention not regulated by the

FDA, e.g., behavioral interventions. This definition of ``clinical

trial'' \4\ is broader than the term ``applicable clinical trial'' as

defined in the regulation.\5\

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    \3\ Further information about this definition is available from

the NIH Office of Science Policy at http://osp.od.nih.gov/office-clinical-research-and-bioethics-policy/clinical-research-policy/clinical-trials.

    \4\ Note that the regulation also includes a definition of

``clinical trial.'' That definition is ``a clinical investigation or

a clinical study in which human subject(s) are prospectively

assigned, according to a protocol, to one or more interventions (or

no intervention) to evaluate the effect(s) of the intervention(s) on

biomedical or health related outcomes'' (see 42 CFR 11.10 (a)). For

the purposes of this policy, the regulatory definition and the

definition in this policy are treated as synonymous.

    \5\ In the regulation, applicable clinical trial is defined as

an applicable device clinical trial or an applicable drug clinical

trial. The regulation defines an applicable device clinical trial to

mean, in part, ``a prospective clinical study of health outcomes

comparing an intervention with a device product subject to section

510(k), 515, or 520(m) of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 360(k), 21 U.S.C. 360e, 21 U.S.C. 360j(m)) against a

control in human subjects (other than a small clinical trial to

determine the feasibility of a device product, or a clinical trial

to test prototype device products where the primary outcome measure

relates to feasibility and not to health outcomes).'' The regulation

defines an applicable drug clinical trial to mean, in part, ``a

controlled clinical investigation, other than a phase 1 clinical

investigation, of a drug product subject to section 505 of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) or a biological

product subject to section 351 of the Public Health Service Act (42

U.S.C. 262), where ``clinical investigation'' has the meaning given

in 21 CFR 312.3 (or any successor regulation) and ``phase 1'' has

the meaning given in 21 CFR 312.21 (or any successor regulation).''

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    Responsible Party. In the policy, the awardee or the investigator

is responsible for meeting the expectations of this policy. In the

regulation, a ``responsible party'' means, in part, ``with respect to a

clinical trial, the sponsor of the clinical trial, as defined in 21 CFR

50.3 (or any successor regulation); or the principal investigator of

such clinical trial if so designated by a sponsor, grantee, contractor,

or awardee, so long as the principal investigator is responsible for

conducting the trial, has access to and control over the data from the

clinical trial, has the right to publish the results of the trial, and

has the ability to meet all of the requirements under [42 CFR part 11]

for the submission of clinical trial information.'' \6\

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    \6\ See 42 CFR 11.10 (a) and 42 CFR 11.4.

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    Primary Completion Date. In the policy, this term has the same

meaning as the term ``primary completion date'' in the regulation,

which is ``the date that the final subject was examined or received an

intervention for the purposes of final collection of data for the

primary outcome, whether the clinical trial concluded according to the

pre-specified protocol or was terminated.'' \7\

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    \7\ See the complete definition at 42 CFR 11.10 (a).

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    Registration Information. In the policy, this term has the same

meaning as the term ``registration information'' in the regulation. In

the regulation, registration information consists of descriptive

information, recruitment information, location and contact information,

and administrative data.\8\

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    \8\ See 42 CFR 11.10 (b) and 42 CFR 11.28 for the specific data

elements.

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    Results Information. In the policy, this term has the same meaning

as the term ``results information'' in the regulation. In the

regulation, results information includes participant flow, demographic

and baseline characteristics, outcomes and statistical analyses,

adverse events, the protocol and statistical analysis plan, and

administrative information.\9\

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    \9\ See 42 CFR 11.28 for complete results information and

specific data elements.

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Compliance

    If the clinical trial is NIH-funded in whole or in part,

expectations for clinical trial registration and summary results

submission will be included in the terms and conditions of the award.

Failure to comply with the terms and conditions of the NIH award may

provide a basis for enforcement actions, including termination,

consistent with 45 CFR 75.371 and/or other authorities, as appropriate.

If the NIH-funded clinical trial is also an applicable clinical trial,

non-compliance with the requirements specified in 42 U.S.C. 282(j) and

42 CFR part 11 may also lead to the actions described in 42 CFR 11.66.

Effective Date

    This policy is effective January 18, 2017.